An alternative synthesis of (±)-phenylephrine hydrochloride

Abstract

This study presents alternative synthetic pathways and reagents for the preparation of racemic phenylephrine hydrochloride. Using m-hydroxybenzaldehyde as starting material, two separate pathways -- epoxidation and bromohydrin formation -- are presented. Both routes provide good yields overall of 71% and 66% respectively, and can be performed at mild conditions.

Headnote

Abstract: This study presents alternative synthetic pathways and reagents for the preparation of racemic phenylephrine hydrochloride. Using m-hydroxybenzaldehyde as starting material, two separate pathways__epoxidation and bromohydrin formation__are presented. Both routes provide good yields (overall of 71% and 66% respectively) and can be performed at mild conditions.

Keywords: phenylephrine, phenylephrine hydrochloride, m-hydroxybenzaldehyde, alpha adrenergic receptor agonist

INTRODUCTION

Phenylephrine hydrochloride (PE) or 3-(1-hydroxy-2-(methylamino)ethyl)phenol hydro- chloride (1: Figure 1) is an alpha1-adrenergic receptor agonist [1] used as a topical nasal decongestant and in eye drops to dilate the pupil. Recently, PE has been marketed in the optically active (R)-form as a substitute for pseudoephedrine, a precursor in the production of methamphetamine, a notorious narcotic drug [2]. Various methods for the synthesis of PE have been documented in the literature. Legerlotz [3-5] reported the classical industrial synthetic pathway. Racemic PE was resolved using tartaric acid in order to obtain the (R)-form [6].

Nonchiral synthesis of PE was reported in 1951 by Bergmann and Sulzbacher [7], who used m-hydroxybenzaldehyde as starting material and a Curtius rearrangement of a beta-hydroxyl acid azide as the key step (Scheme 1). In 1961, Russell and Childress [8] used the same starting material for the synthesis of racemic PE, employing the reduction of mandelamide with lithium aluminium hydride as the key step (Scheme 2). Takeda et al. [9] reported an asymmetric synthesis of chiral PE using (2R,4R)-dicyclohexylphosphino-2-diphenylphosphinomethyl-1-(N-methycarbonyl)-pyrolidine (MCCPM)-rhodium as chiral catalyst, producing (R)-PE as a product with 85% ee (Scheme 3).

McGarrity and Zanotti-Gerosa [10] reported a feasibility study on a new route to (R)-PE based on ruthenium-derivative-catalysed asymmetric hydrogenation of an N-protected aminoketone precursor (Scheme 4). The direct and fast asymmetric reduction of N-protected aminoketone was highly enantioselective (>95% ee) but the (S)-PE was the main product in most conditions.

Gurjar et al. [11] studied the hydrolytic kinetic resolution of a styrene oxide derivative. They used (R,R)-SalenCoIIIOAc complex to induce racemic styrene epoxide to (R)-form at 45% yield (97% ee) as shown in Scheme 5 [11]. In 2003, Pandey et al. [13] reported (R)-PE synthesis via Sharpless asymmetric dihydroxylation with 98% ee, yielding the desired product in seven steps (Scheme 6). In this paper, we report a variation of the route and reagents for preparing PE in high yields using mild conditions.

DISCUSSION

Synthesis of PE (1) was initiated from m-hydroxybenzaldehyde (2), as illustrated in Scheme 7. The protection of 2 with t-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole produced the silyl compound 3 in quantitative yield. The Wittig olefination of 3 with methyltriphenylphosphonium iodide and t-BuOK in THF at ambient temperature furnished styrene 4 in 97% yield. After these steps, the synthesis could be performed using two pathways. The epoxidation of 4 with m-chloroperoxybenzoic acid (MCPBA) in CH2Cl2 at room temperature produced epoxide 5 in 81% yield, while treatment of 4 with N-bromosuccinimide (NBS) in the presence of H2O and DMSO at room temperature produced bromohydrin 6 in 80% yield. The epoxide 5 and bromohydrin 6 was treated with methylamine in methanol at room temperature and the TBDMS group deprotected with 6M hydrochloric acid solution at room temperature to produce 1 in 90% (from epoxide 5) and 85% (from bromohydrin 6). The overall yields of 1 via epoxide 5 and bromohydrin 6 were 71% and 66% respectively.

CONCLUSION

A practical and alternative method for the synthesis of racemic phenylephrine hydrochloride has been performed using mild conditions with good overall yields.

EXPERIMENTAL

m-Hydroxybenzaldehyde, TBDMS-Cl, MCPBA, imidazole, potassium tert-butoxide and methylamine were purchased from Aldrich. Methyltriphenylphosphonium iodide was prepared from triphenylphosphine and methyl iodide. N-Bromosuccinimide was recrystallised in water at 90o and dried in oven at 60o for 2 hr. All solvents were distilled prior to use. Thin-layer chromatography (TLC) was performed on silica 60 F264 plates and column chromatography was carried out on silica gel (0.063-0.20 mm).

1H-NMR spectra were recorded on a 400-MHz or 500-MHz Bruker Avance using trimethyl- silane as the internal standard in CDCl3 or DMSO-d6. 13C-NMR spectra were recorded on a 100-MHz or 125-MHz Bruker Avance using trimethylsilane as the internal standard in CDCl3 or DMSO-d6. Mass spectra were recorded on ESI-Q-TOF-MS (Micromass, Manchester, UK). IR spectra were recorded on a FT-IR spectrometer (Tensor 27) as neat film or KBr disc. Melting point was determined on MEL-TEMP (Laboratory Devices Inc., USA) and used without correction.

3-(tert-Butyldimethylsilyloxy)benzaldehyde (3)

Imidazole (4.21 g, 61.8 mmol) and TBDMS-Cl (9.31 g, 61.7 mmol) was added to a stirred solution of m-hydroxybenzaldehyde (2) (5.04 g, 41.3 mmol) in dry dichloromethane (50 mL) at 0o. The mixture was then allowed to warm up to room temperature. After 24 hr, water (30 mL) was added and the organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified on silica gel by eluting with EtOAc-hexane (1:4) to give compound 3 as a pale yellow liquid (10.13 g, quantitative yield): IR 2958, 2927, 2860, 1705, 1581, 1275, 840 cm-1; 1H-NMR δ 9.94 (s, 1H), 7.46 (dt, J = 7.5, 1.3 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 2.3, 1.6 Hz, 1H), 7.10 (m, 1H), 0.99 (s, 9H), 0.22 (s, 6H); 13C-NMR δ 191.85, 156.27, 137.85, 129.95, 126.37, 123.43, 119.69, 25.52, 18.05, -4.58; HRMS calculated for C13H21O2Si [M+H]+ 237.1311, found 237.1313.

tert-Butyldimethyl(3-vinylphenoxy)silane (4)

Potassium tert-butoxide (2.90 g, 25.9 mmol) was added to a stirred suspension of methyltriphenylphosphonium iodide (10.32 g, 25.5 mmol) in dry THF (50 mL) at 0o. The mixture was stirred at room temperature for 1 hr; then aldehyde 3 (5.01 g, 21.2 mmol) was added portionwise. The mixture was stirred for 2 hr at room temperature and diluted with water (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified on silica gel by eluting with EtOAc-hexane (1:19) to furnish, after concentration, compound 4 (4.82 g, 97%) as a colourless liquid: IR 2957, 2930, 2858, 1578, 1485, 1279, 839 cm-1; 1H-NMR δ 7.27 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.6 Hz), 7.02 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 17.5, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H), 1.12 (s, 9H), 0.33 (s, 6H); 13C-NMR δ 155.84, 139.06, 136.75, 129.36, 119.51, 119.49, 117.72, 113.78, 25.69, 18.17, -4.42; HRMS calculated for C14H23O2Si [M+H]+ 235.1518, found 235.1512.

tert-Butyldimethyl(3-oxiranylphenoxy)silane (5)

MCPBA (1.01 g, 5.83 mmol) was added to a stirred solution of compound 4 (0.65 g, 2.76 mmol) in CH2Cl2 (15 mL) at room temperature. After 3 hr, the reaction mixture was washed with saturated sodium thiosulfate solution (5 mL) and saturated NaHCO3 solution (5 mL). The organic layer was washed with brine (5 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified on silica gel by eluting with EtOAc-hexane (1:19) to produce, after concentration, compound 5 (0.56 g, 81%) as a colourless liquid: IR 3048, 2931, 2858, 1606, 1486, 1284, 957, 833 cm-1; 1H-NMR δ 7.20 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.3 Hz, 2H), 3.79 (dd, J = 4.0, 2.6 Hz, 1H), 3.09 (dd, J = 5.6, 4.1 Hz, 1H), 2.74 (dd, J = 5.6, 2.5 Hz, 1H), 1.03 (s, 9H), 0.23 (s, 6H); 13C-NMR δ 155.80, 139.24, 129.30, 119.64, 118.42, 116.74, 51.87, 50.82, 25.51, 17.99, -4.60; HRMS calculated for C14H23O2Si [M+H]+ 251.1467, found 251.1465.

2-Bromo-1-(3-(tert-butyldimethylsilyloxy)phenyl)ethanol (6)

NBS (1.14 g, 6.43 mmol) and water (0.25 mL) were added to a stirred solution of compound 4 (0.52 g, 2.22 mmol) in DMSO (8 mL) at 0°C. After 45 min., ice-cooled water (10 mL) was added. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with brine (5 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified on silica gel by eluting with EtOAc-hexane (1:19) to produce, after concentration, compound 6 (0.59 g, 80%) as a colourless liquid: IR 3422, 2956, 2858, 1602, 1485, 1065, 1278, 835 cm-1; 1H-NMR δ 7.22 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.88 (br, 1H), 6.80 (d, J = 8.0 Hz, 1H), 4.85 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 9.1, Hz, 1H), 3.51 (t, J = 9.7 Hz, 1H), 2.77 (s, 1H), 1.00 (s, 9H), 0.21 (s, 6H); 13C-NMR δ 155.85, 141.89, 129.59, 119.98, 118.79, 117.69, 73.51, 40.04, 25.62, 18.12, -4.45; HRMS calculated for C14H23O1SiBr [M+H-OH]+ 315.0630, found 315.0346.

Phenylephrine hydrochloride (1)

Via epoxide compound 5

A solution of 5 (0.51 g, 2.05 mmol) in dry methanol (5 mL) was saturated with methylamine gas and left stirred at room temperature for 2 hr. The solution was concentrated to give the crude mixture. Hydrochloric acid (6M, 0.50 mL) was added to the solution of the crude mixture in methanol (5 mL). The resulting solution was stirred at room temperature for 2 hr and then concentrated under reduced pressure. The residue was purified on silica gel by eluting with methanol:dichloromethane (1:19) to produce, after concentration, PE (1) (0.38 g, 90%) as a white solid: m.p.141-143o (Lit.141o [11]); IR 3419, 2963, 2798, 1593, 1462, 1274, 1083, 879 cm-1; 1H- NMR δ 9.56 (s, 1H), 8.99 (br, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.81 (br, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 4.83 (d, J = 8.3 Hz, 1H), 3.05 (d, J = 12.5 Hz, 1H), 2.11 (t, J = 12.4 Hz, 1H), 2.53 (s, 3H); 13C-NMR δ 157.99, 143.71, 129.78, 116.74, 115.12, 113.22, 68.49, 55.37, 33.14; HRMS calculated for C9H14NO2 [M+H]+ 168.0980, found 168.1019.

Via bromohydrin compound 6

A solution of bromohydrin 6 (0.53 g, 1.60 mmol) in dry methanol (5 mL) was processed under the same procedure as above to produce 1 (0.29 g, 85%).

ACKNOWLEDGEMENTS

We thank the Development and Promotion of Science and Technology Talents Project (DPST), the Graduate School and the Department of Chemistry, Chiang Mai University for their financial support.

References

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